1,721,025 research outputs found
Connective Tissue Growth Factor and Its Role in Lung Adenocarcinoma Invasion and Metastasis
No full text惡性程度較高的癌細胞通常表現出較高的浸襲力，抗無貼附狀態細胞凋亡、血管新生及遠端轉移能力。一些CCN家族或成員已被報導可調控上述表現型，結締組織生長因子於正常肺膜上皮細胞表現量相當高，本論文在探究結締組織生長因子是否介入調控人類細胞轉移的能力。
過度表現結締組織生長因子於CL1-5及A549的人類肺腺癌細胞株能有意義地降低癌細胞的浸襲力及遠端肺轉移率，在結締組織生長因子轉殖株中，神經塌陷因子呈現有意義的上升。加入integrin αvβ3及αvβ5抑制劑能阻斷結締組織生長子造成的神經塌陷因子上升現象，而處理神經塌陷因子的反核數序列株，則可回復因結締組織生長因子造成的浸襲力降低。實驗中發現，單獨使用結締組織生長因子的CT功能區段便能造成神經塌陷因子增加，並有效抑制肺癌細胞的浸襲。臨床上分析結締組織生長因子蛋白表現量較低的病人，與癌病惡性度較高，有淋巴轉移，較早癌病復發率及較短存活時間有正相關。因為癌細胞轉移的第一個步驟是自原病灶脫離，而能與血路中存活，我們分析結締組織生長因子是否也在此步驟中扮演促進細胞凋亡的角色，而造成轉移的抑制。在第三章中，我們分析高表現結締組織生長因子的肺癌細胞株，對無貼狀態引起的細胞凋亡較明顯，而內生性的死亡相關蛋白量也較高。
在結締組織生長因子轉殖株中，死亡相關蛋白呈現有意義的上升，實驗中發現若轉殖死亡相關蛋白反序列質體入結締組織生長因子轉殖株，則可降低因無貼附狀態而誘發的細胞凋亡現象，且是經由抑制了ERK/Elk-1之訊息傳遞路徑，如同第二章的結果，只需CT區段的結締組織生長因子便能有效造成死亡相關蛋白的上升，而造成無貼附狀態的肺癌細胞株細胞凋亡。
根據之前的實驗結果，肺癌細胞病人腫瘤大小與結締組織生長因子的表現量有反相關，於是在第四章中，我們試圖探究結締組織生長因子與腫瘤發生及血管新生的關係。病患切片中可見高結締組織生長因子表現量的檢體，血管內皮生長因子及微血管的數量則明顯較低。細胞離體實驗則證明，結締組織生長因子蛋白能抑制血管內皮生長因子及缺氧誘發因子的蛋白及傳訊RNA的表現量。我們亦進行動物腫瘤生長及血管新生實驗來證明結締組織生長因子確能抑制血管新生現象，作用是藉由活化ARD1造成缺氧誘發因子基因的乙醯化，而使該蛋白趨向不穩定所致。
總結來說，本論文提供了結締組織生長因子可抑制人類肺腺癌轉移及血管新生的證據；作為一個癌細胞浸襲抑制蛋白，無貼附狀態細胞凋亡促進者，及血管新生抑制蛋白，結締組織生長因子作為臨床治療的蛋白質類藥物，是相當具潛力而可期待的。Advanced cancer cells show higher invasive, anti-anoikis, angiogenesis, and metastatic abilities. Several members of CCN [CTGF (connective tissue growth factor), Cyr61 (cysteine-rich 61), Nov (nephroblastoma overexpressed)] family can modulate these phenotypes of human carcinoma. CTGF is highly expressed in normal lung epithelium. We investigated the possibility that CTGF may regulate human lung adenocarcinoma metastasis activities.
Overexpression of CTGF in CL1-5 and A549 cells decreased invasiveness and lung metastasis relative to control cells. CTGF-mediated CRMP-1 (collapsin response mediator protein-1) up-regulation was also noted in CTGF transfected clones, and was inhibited by anti-integrin AvB3 and AvB5 antibodies. Significantly, suppression of CRMP-1 expression by antisense oligonucleotides increased invasive ability. We also clarified the CT domain of CTGF as the major component responsible for CRMP-1 up-regulation and invasion inhibition. Immunohistochemistry of lung cancer specimens showed that reduced expression of CTGF was statistically significantly associated with advanced disease, lymph node metastasis, early postoperative relapse, and shorter survival.
Because the first step of metastasis is to detach from the primary tumor mass and survive in the bloodstream, we analyzed several lung cancer cell lines which expressed different levels of CTGF undergo apoptosis in anoikis condition in order to understand whether CTGF is involved in anoikis regulation. In the chapter 3, we demonstrated that highly CTGF expressed cells showed increased sensitivity to anoikis, and were correlated with the expression of DAPK (death associated protein kinase), a newly identified protein kinase associated with apoptosis. We further found DAPK is upregulated in CTGF-overexpressed clones, and transiently transfected dominant-negative DAPK diminished DNA fragmentation after detachment in CTGF-overexpressed clones. The CT module of CTGF was also the region primarily responsible for the induction of DAPK via ERK/Elk-1 signaling pathway.
In chapter 4, due to the significant inverse correlation between CTGF expression and tumor size in lung adenocarcinoma patients ( P < 0.041 ), we investigated the angiogenic and tumorigenic potential of CTGF-overexpressed CL1-5 lung adenocarcinoma cells. We identified consistently inverse correlation between CTGF and VEGF (vascular endothelial growth factor) or CD31 staining in cancerous tissue than in adjacent noncancer part in lung adenocarcinoma patient. In vitro study showed that CTGF inhibited VEGF, and HIF-1a (hypoxia-inducible factor) mRNA and protein expression, and decreased HRE (hypoxia-response element) luciferase activities. We further identified that CTGF inhibited in vivo tumor growth and in vitro and in vivo angiogenesis of lung adenocarcinoma cell lines. At molecular level, CTGF inhibited HIF-1a expression via destabilization of HIF-1a by ARD1-mediated acetylation.
In summary, these studies provide evidences for the tumor metastasis suppressing effect of CTGF in the lung adenocarcinoma. Herein, as an invasion blocker, anoikis promoter and angiogenesis inhibitor that specifically targets cancer cells, CTGF has a unique potential for lung adenocarcinoma treatment.中文摘要 (Abstract in Chinese) 3
英文摘要 (Abstract in English) 5
第一章 序論 (Introduction) 7
第一節 人類肺腺癌 (Human lung adenocarcinoma) 8
第二節 結締組織生長因子 (Connective tissue growth factor) 11
第三節 本論文的研究動機與方向 (Motivation and purpose in the thesis) 13
第四節 參考文獻 (Reference) 14
第二章 結締組織生長因子抑制人類肺腺癌細胞之浸襲及轉移 (Connective tissue growth
factor and its role in lung adenocarcinoma invasion and metastasis) 18
第一節 摘要 (Abstract) 19
第二節 前言 (Introduction) 21
第三節 材料與方法 (Materials and Methods) 23
第四節 實驗結果 (Results) 32
第五節 討論 (Discussion) 40
第六節 參考文獻 (Reference) 45
第七節 附圖及說明 (Figures and figure legends) 51
第三章 結締組織生長因子提高人類肺腺癌細胞對無貼附狀態之細胞凋亡敏感度 (Connective tissue growth factor increased human lung adenocarcinoma cells anoikis sensitivity) 65
第一節 摘要 (Abstract) 66
第二節 前言 (Introduction) 68
第三節 材料與方法 (Materials and Methods) 70
第四節 實驗結果 (Results) 80
第五節 討論 (Discussion) 92
第六節 參考文獻 (Reference) 96
第七節 附圖及說明 (Figures and figure legends) 101
第四章 結締組織生長因子透過促進缺氧誘發因子降解以抑制癌細胞之血管新生 (Connective tissue growth factor inhibited angiogenesis by accelerating HIF-
Vascular endothelial growth factor-A and changes in a tumor-bearing mouse model with Lewis lung cancer
No full textLysophosphatidic acid upregulates vascular endothelial growth factor-C and tube formation in human endothelial cells through LPA1/3, COX-2, and NF-κB activation- and EGFR transactivation-dependent mechanisms
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Non-invasive ultrasound in the study of recombinant CTGF-CT therapy in mice gastric cancer model
No full textVariations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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